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[edit] Summary
This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.
[edit] Description
HER2/neu (also known as ErbB-2) is a member of the ErbB protein family, more commonly known as the epidermal growth factor receptor family. HER2/neu is notable for its role in the pathogenesis of breast cancer and as a target of treatment. It is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. HER2 is thought to be an orphan receptor, with none of the EGF family of ligands able to activate it. However, ErbB receptors dimerise on ligand binding, and HER2 is the preferential dimerisation partner of other members of the ErbB family.[1] The HER2 gene is a proto-oncogene located at the long arm of human chromosome 17(17q11.2-q12).
Approximately 25-30 percent of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product. Overexpression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis. Because of its prognostic role as well as its ability to predict response to trastuzumab (see below), breast tumors are routinely checked for overexpression of HER2/neu. Overexpression also occurs in other cancer such as ovarian cancer and stomach cancer.
The oncogene neu is so-named because it was derived from a neuroglioblastoma cell line in rat. HER2 is named because it has similar structure to human epidermal growth factor receptor, or HER1. ErbB2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Gene cloning showed that neu, HER2, and ErbB2 were the same.
Clinically, HER2/neu is important as the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is only effective in breast cancer where the HER2/neu receptor is overexpressed.
HER2 is co-localized, and thus most of the time co-amplified with the gene GRB7, which is as well a proto-oncogene (active in e.g. breast cancer, testicular germ cell tumour, gastric cancer, and esophageal cancer).
The HER2 gene overexpression can be suppressed by the amplification of other genes and the use of the drug Herceptin. Research is currently being conducted to discover which disregulated genes may have this desired effect. Another monoclonal antibody, pertuzumab [3], which inhibits dimerization of HER2 and HER3 receptors, is in advanced clinical trials.
[edit] References
- ^ Olayioye MA (2001). "Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members". Breast Cancer Res 3 (6): 385-389. doi:10.1186/bcr327. PMID 11737890.
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